Role of n-methyl pyrrolidone in the enhancement of aqueous phase transdermal transport

The role of n-methyl pyrrolidone (NMP) as an enhancer for permeants delivered from an aqueous phase was investigated in the transdermal delivery of the local anesthetics lidocaine free base, lidocaine-hydrochloride (HCl), and prilocaine-HCl. Lidocaine free-base flux increased from H2O/NMP binary systems containing over 50% (v/v) NMP with significant flux enhancement observed above 80% NMP. In this range, drug flux was found to correlate with NMP flux. The addition of oleic acid (1% w/v) further enhanced lidocaine flux sixfold, in these formulations. The H2O/NMP (50% v/v) system enhanced the transport of water-soluble hydrochloride salt derivatives of lidocaine and prilocaine by factors of 4.3 and 2.6, respectively, indicating that NMP was capable of enhancing hydrophilic and hydrophobic drugs from an aqueous phase. These findings were consistent with the model that NMP flux across the stratum corneum improves the transport of formulation solutes.     

Novel Microemulsion Enhancer Formulation for Simultaneous Transdermal Delivery of Hydrophilic and Hydrophobic Drugs

Purpose. Microemulsion (ME) systems allow for the microscopic co-incorporation of aqueous and organic phase liquids. In this study, the phase diagrams of four novel ME systems were characterized. Methods. Water and IPM composed the aqueous and organic phases respectively, whereas Tween 80 served as a nonionic surfactant. Transdermal enhancers such as n-methyl pyrrolidone (NMP) and oleyl alcohol were incorporated into all systems without disruption of the stable emulsion. Results. A comparison of a W/O ME with an O/W ME of the same system for lidocaine delivery indicated that the O/W ME provides significantly greater flux (p < 0.025). The water phase was found to be a crucial component for flux of hydrophobic drugs (lidocaine free base, estradiol) as well as hydrophilic drugs (lidocaine HCl, diltiazem HCl). Furthermore, the simultaneous delivery of both a hydrophilic drug and a hydrophobic drug from the ME system is indistinguishable from either drug alone. Enhancement of drug permeability from the O/W ME system was 17-fold for lidocaine free base, 30-fold for lidocaine HCl, 58-fold for estradiol, and 520-fold for diltiazem HCl. Conclusions. The novel microemulsion systems in this study potentially offers many beneficial characteristics for transdermal drug delivery.     

Cremophor RH40-PEG 400 microemulsions as transdermal drug delivery carrier for ketoprofen

The aim of this study was to prepare novel microemulsion for transdermal drug delivery of ketoprofen (KP). The microemulsion composed of ketoprofen as model drug, isopropyl myristate (IPM) as oil phase, surfactant mixture consisting of polyoxyl 40 hydrogenated castor oil (Cremophor RH40) as surfactant and polyethylene glycol 400 (PEG400) as co-surfactant at the ratio 1:1, and water were prepared. The viscosity, droplet size, pH, conductivity of microemulsions, and skin permeation of KP through shed snake skin were evaluated. The particle size, pH, viscosity and conductivity of microemulsions were in the range of 114-210 nm, 6.3-6.8, 124-799 cPs and 1-45 μS/cm, respectively. The ratio of IPM, and surfactant mixture played the important role in the skin permeation of KP microemulsions. As the amount of surfactant mixture and IPM increased, the skin permeation of KP decreased. The formulation composed of 30% IPM, 45% surfactant mixture and 25% water showed the highest skin permeation flux. The incorporation of terpenes in the 2.5% KP microemulsions resulted in significant enhancement in skin permeation of KP. The rank order of enhancement ratio for skin permeation enhancement of terpenes was α-pinene > limonene > menthone. The results suggested that the novel microemulsion system containing IPM, water, Cremophor RH40:PEG400 and terpenes can be applied for using as a transdermal drug delivery carrier.     

Effects of solvents on skin permeation of formoterol fumarate

Effects of various chemicals applied as penetration enhancers on the permeation of formoterol fumarate (FF) across excised rat skin were investigated. Remarkable enhancement was noted with terpenes, fatty acid esters, and higher alcohols, whereas no significant influence was observed in the case of lower alcohols, pyrrolidones, and amines. At high concentration, a cineole/N-methyl-2-pyrrolidone (NMP) mixed solvent system slightly enhanced the skin permeation of FF compared with cineole alone, and a l-menthol/NMP mixed solvent system caused significant further increase. Maximum skin permeation of FF was seen when the ratio of l-menthol/NMP was 60/40 w/w. From the present results, l-menthol/NMP and isopropyl myristate (IPM)/NMP mixed solvent systems can be considered effective for augmenting skin permeation of FF, with potential applications in transdermal delivery of the drug.     

Investigations on the Percutaneous Absorption of the Antidepressant Rolipram in Vitro and in Vivo

In vitro experiments using full-thickness human skin showed that it was feasible to deliver therapeutic amounts of the new antidepressant drug rolipram. Simple transdermal devices were constructed, and the presence of isopropyl myristate (IPM) in a silicone adhesive (Dow Corning X7-2920) enhanced the flux across excised human skin. The steady-state fluxes from adhesive mixtures containing 0, 5, and 10% IPM were 3, 5.2, and 6 µg/cm²/hr, respectively. The in vitro experiments were confirmed in a clinical study involving six healthy male volunteers. The formulations tested were an alcoholic solution and adhesive patches containing 5 and 10% IPM. The dose of drug administered was 0.5 mg/cm² and the device size 25 cm². Blood samples were withdrawn over a 24-hr period and analyzed using radioimmunoassay. The topical applications were well tolerated, with only mild or no side effects. A lag time of approximately 2 hr was found for the detection of rolipram in the plasma (detection limit, 50 pg/ml). Interindividual variations both for the peak drug levels and throughout the delivery were quite high but this magnitude of variation has been observed in many other transdermal studies. Plasma levels between 1 and 2 ng/ml were found for all formulations and the AUC_0–30hr was significantly higher for the patch containing 5% IPM.     

Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement

Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the permeation constant, while the values of lag time were reversed. The ternary mixture was then selected as a potential absorption enhancement vehicle for the transdermal delivery of drug. In general, higher fluxes were observed through hairless guinea pig skin as compared with the human stratum corneum. Based on the results obtained from the release study of NC-HCl from saturated solutions of the drug, a novel lecithin organogel (microemulsion-based gel) composed of soybean lecithin, propylene glycol, oleic acid, dimethyl isosorbide, and isopropyl myristate was developed as a possible matrix for transdermal delivery of NC-HCl. In vitro percutaneous penetration studies from this newly developed gel system through giunea pig skin and human stratum corneum revealed that the organogel system has skin-enhancing potential and could be a promising matrix for the transdermal delivery of nicardipine. Furthermore, higher permeation rates were observed when nicardipine free base was incorporated into the gel matrix instead of hydrochloride salt.     

In vivo immunomodulatory, cumulative skin irritation, sensitization and effect of d-limonene on permeation of 6-mercaptopurine through transdermal drug delivery

Using skin as a port for systemic drug administration, transdermal drug delivery has expanded greatly over the last two decades. Our aim was to formulate the single layer drug-in-adhesive transdermal patch for 6-mercaptopurine (6-MP). In vitro permeation study was carried out using modified Franz diffusion cell with and without of different concentration of d-limonene in human cadaver skin. In vivo immunomodulatory was carried out in mice, cumulative skin irritation, sensitization and patch adherence study was done in both mice and human subjects. 6-MP flux increased from 43+/-12.2 microg/cm2h (control) to 162.8+/-32.2 microg/cm2h (6% w/v d-limonene) data was significant (p<0.05), with decrease in the lag time to 35+/-9.3 min compared to control of 90 +/-15.3 min. In vivo immunomodulatory effect was shown in the Balb/c mice with 100 mumol/kg/body wt of animal for 5d (one dose/d) of d-limonene. WBC count of 13469 cells/mm peak was observed on 12th day, bone marrow cells of 26.3 x 10(6) cells/femur and alpha-esterase positive cells of 1259+/-328.4 cells/4000 bone marrow cells. Cumulative skin irritation, sensitisation and patch adherence in animals and human subjects showed no skin irritation and sensitization. Patch adhesion was greater than 90.0% respectively in both human subjects and mice. The percentage of human subjects with adhesive residue was significantly less with scores of zero. d-Limonene proved as good chemical enhancer by increasing in the skin permeability with shortened the lag time. It proved that therapeutic amount of 6-MP can be delivered through transdermal drug delivery.     

Formulation and in vitro evaluation of pentazocine transdermal delivery system

The aim of this study was to prepare a pentazocine (PTZ) matrix-type transdermal drug delivery system (TDDS) using acrylic pressure-sensitive adhesives. Among the five Duro-Tak adhesive polymers tested (87-9301, 87-2677, 87-201A, 87-2196, 87-2852), in vitro dissolution studies demonstrated the highest PTZ release flux from the Duro-Tak 87-9301 matrix. In addition, the effects of permeation enhancers, isopropyl myristate (IPM) and glyceryl monocaprylate (GEFA-C(8)), and drug content on PTZ skin permeation from prepared patches were evaluated using Franz diffusion cells fitted with hairless mouse skin. IPM and GEFA-C(8) were found to produce effective flux of PTZ at a patch concentration of 10% w/w and 5% w/w, respectively. The PTZ flux increased linearly as the loading dose increased up to 30%, whereas no further increase in flux was observed at loading doses of 40% and 50% due to drug crystallization in the matrix. Thus, the highest skin permeation rate (24.2 microg/cm(2)/h) was achieved when 30% of PTZ was loaded in Duro-Tak 87-9301 with 10% IPM and 5% GEFA-C(8). These results demonstrate the feasibility of a novel narcotic-antagonist analgesic matrix-type TDDS for PTZ.     

Transdermal delivery of antiparkinsonian agent, benztropine. I. Effect of vehicles on skin permeation

The influence of pH and various lipophilic and hydrophilic vehicles on the epidermal permeation of benztropine (BZ) free base and its mesylate salt were studied in vitro using the hairless mouse (HLM) and human cadaver (HC) skin membranes. The pH-partition behavior of BZ base (pK(a)=10) was examined using n-octanol and Britton-Robinson buffers over the pH range of 5-12. Unexpectedly, the ionized species of BZ yielded a high partition coefficient (log K(octanol/water)=2. 14), which was reflected by its relatively high skin permeability (P=1.6x10(-2)cm h(-1)). BZ base delivered from a lipophilic vehicle with a solubility parameter range of 7.1-10.3 (cal cm(3))(1/2) exhibited a significantly enhanced rate of permeation as compared to that attained from a hydrophilic vehicle of solubility parameter range between 12.5-23.4 (cal cm(3))(1/2). Among the neat solvents examined, a lipophilic carrier, isopropyl myristate (IPM) provided the most enhancing effect on the permeation of BZ base. In addition, the neat IPM carrier offered the maximum BZ base flux of 150 microg per cm(2) h(-1) across HC skin, which was approximately 16 times greater than the target delivery rate of BZ from a 10-cm(2) device. In comparison, BZ base exhibited a 2-60 times greater flux than BZ mesylate when delivered from the neat solvents. However, interestingly enough, the binary cosolvents consisting of IPM and short-chain alkanols such as ethanol (EtOH), isopropanol (iPrOH), and tertiary butanol (tBtOH), in particular a 2:8 combination, produced a marked synergistic enhancement of BZ flux from the mesylate salt, whereas a retarding effect was noticed for the permeation of BZ base. The enhancement potency for the BZ mesylate permeation increased linearly with the carbon number of the branched alcohols present in the binary mixtures. A tBtOH-IPM (2:8) combination produced the highest BZ flux from the mesylate salt, i.e. , 2016 mg per cm(2) h(-1), which was 100-fold greater than from water and 44-540-fold greater than the individual neat solvents, respectively. The observed permeation enhancement of BZ mesylate by the alkanol-IPM mixtures was probably as a result of a combination of decreasing barrier ability of the stratum corneum by the binary vehicles and moderately partitioning BZ mesylate through the viable epidermis/dermis.     

Transdermal Delivery of Levonorgestrel. V. Preparation of Devices and Evaluation in Vitro

Transdermal devices were prepared and evaluated for their ability to codeliver levonorgestrel and the permeation enhancers ethyl acetate and ethanol in vitro. The 24-hr devices were prepared with membranes composed of ethylene vinyl acetate (EVAc) copolymers. The vinyl acetate (VAc) content of the membranes (50 ± 10 or 100 ± 10 µm thick) was varied from 12 to 25% to give a range of permeabilities toward the enhancers. The reservoir used was ethyl acetate/ethanol (7:3, v/v; 0.5 ml) containing excess solid levonorgestrel and gelled with 2% hydroxypropyl cellulose. The higher VAc content membranes (18 and 25%) exhibited relatively high release rates of EtAc and EtOH leading to depletion of ethyl acetate and ethanol from the reservoir by the end of 24 hr. As a result, the transdermal flux of levonorgestrel, evaluated using rat skin, reached a maximum at about 8 hr and thereafter diminished to zero by 24 hr. The less permeable membranes (12 and 15% VAc content) led to a more sustained release of enhancers, but due to lower solvent delivery to the skin, levonorgestrel flux was substantially lower. There was a direct relationship between drug delivery through skin and the amount of solvent delivered until release of the enhancers had diminished. The potential use of ethyl acetate in transdermal drug delivery is also discussed.     

Microemulsion-based gel of fluorouracil for transdermal delivery

This study is to prepare the microemulsion-based gel based on the W/O microemulsion and fluorouracil (5-Fu) as a model drug to study the transdermal characterization and observe its skin irritation of the microemulsion-based gel in vitro. IPM acted as oil phase, AOT as surfactant, Tween 85 as cosurfactant, water was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, then 5-Fu powder was added. The gelatin was used as substrate to prepare 5-Fu microemulsion-based gel. The permeation flux of 5-Fu from 5-Fu microemulsion-based gel across excised mice skin was determined in vitro using Franz diffusion cell to study the influence of the amount of gelatin and the drug loading capacity. Refer to 5-Fu cream, the irritation of microemulsion and microemulsion-based gel on the rat skin was studied. Based on the water/AOT/Tween 85/IPM microemulsion, only the gelatin can form the microemulsion-based gel. At 25 degrees C, 32 degrees C and 40 degrees C, the amount of gelatin required for the formation of microemulsion-based gel were 7%, 14% and more than 17%, respectively. The 12 h transdermal cumulated permeation amount of 5-Fu from microemulsion-based gel containing 14% gelatin and 0.5% drug loading were (876.5 +/- 29.1) microg x cm(-2), 12.3 folds and 4.5 folds more than 0.5% 5-Fu aqueous solution and 2.5% (w/w) 5-Fu cream, respectively. Microemulsion-based gel exhibited some irritation, but could be subsided after drug withdrawal. Microemulsion-based gel may be a promising vehicle for transdermal delivery of 5-Fu and other hydrophilic drug.     

Formulation of an HPMC gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing in vitro transdermal delivery of nicorandil

The objective of the present study was to formulate a hydroxypropyl methylcellulose (HPMC) gel drug reservoir system with ethanol-water as a solvent system and limonene as a penetration enhancer for enhancing the transdermal delivery of nicorandil so as to develop and fabricate a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation of nicorandil was determined across rat abdominal skin from a solvent system consisting of ethanol or various proportions of ethanol and water. The ethanol-water (70:30 v/v) solvent system that provided an optimal transdermal permeation was used in formulating an HPMC gel drug reservoir system with selected concentrations (0% w/w, 4% w/w, 6% w/w, 8% w/w or 10% w/w) of limonene as a penetration enhancer for further enhancement of transdermal permeation of nicorandil. The amount of nicorandil permeated in 24 h was found increased with an increase in the concentration of limonene in the drug reservoir system up to a concentration of 6% w/w, but beyond this concentration there was no further increase in the amount of drug permeated. The flux of nicorandil was 370.9 +/- 4.2 microg/cm2 x h from the drug reservoir system with 6% w/w of limonene, which is about 2.6 times the required flux to be obtained across rat abdominal skin for producing the desired plasma concentration for the predetermined period in humans. The results of a Fourier Transform Infrared study indicated that limonene enhanced the percutaneous permeation of nicorandil by partially extracting the stratum corneum lipids. It is concluded that the HPMC gel drug reservoir system prepared with a 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene is useful in designing and fabricating a membrane-moderated TTS of nicorandil.     

Formulation optimization and stability study of transdermal therapeutic system of nicorandil

The aim of this research investigation was to fabricate acrylate-based stable transdermal therapeutic system (TTS) of nicorandil, which could deliver drug through transdermal route. Monolithic TTS was fabricated in pressure sensitive adhesives (PSAs)--(a) terpolymer (PSA1) of 2-ethylhexyl acrylate, methyl methacrylate, and acrylic acid, (b) copolymer (PSA2) of 2-ethylhexyl acrylate, methyl methacrylate, acrylic acid, and vinyl acetate, and (c) Eudragit E100 pressure sensitive adhesive (PSA3). To enhance the flux of nicorandil, skin permeation enhancer N-methyl-2-pyrrolidone (NMP) was investigated at different concentrations (0.05-5%) in PSAs. Fabricated TTS was evaluated for in-vitro release and skin permeation through guinea pig skin. Maximum flux of nicorandil was observed from Eudragit E100 based TTS and kept for stability study at refrigeration, 25 degrees C/30% RH and 30 degrees C/60% RH. Patches were evaluated for various physicochemical parameters. Formulation was observed to be relatively more stable at refrigeration. Shelf life of the formulation was found to be 270, 270, and 30 days at refrigeration, 25 degrees C/30% RH and 30 degrees C/60% RH conditions, respectively. Nicorandil could be successfully derived from Eudragit E100 based TTS, but attention needs to be given to improve its chemical stability in formulation.     

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.     

Effect of penetration enhancers on skin permeation of trazodone hydrochloride from matrix type transdermal formulation through mouse and human cadaver epidermis

A transdermal dosage form of trazodone hydrochloride (TZN) may be useful in the treatment of moderate to severe depression in schizophrenic patients by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of TZN would attenuate fluctuating plasma level of TZN resulting from oral therapy. The aim of the current investigation was to evaluate its flux and the effects of various penetration enhancers, viz., isopropyl myristate (IPM), isopropyl palmitate (IPP), butanol and octanol on transdermal permeation from matrix-based formulations through the skin. The enhancing effect on the permeation of TZN was determined using the mouse and human cadaver epidermis. In vitro permeation data were collected at 37 degrees C using Keshary-Chien diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation flux of TZN, enhancement ratio and the diffusion parameter. The highest enhancing effect was obtained with IPM followed by butanol, octanol and IPP. In general, higher fluxes were observed through mouse epidermis as compared with the human cadaver epidermis. The skin retention of TZN for both the species in the presence of different enhancers was nearly 3 times higher than for the control formulation. Based on the observed results, a transdermal patch of about 70 cm2 consisting of 10 % IPM should be able to attain and maintain therapeutic plasma concentration of TZN at 0.75 mg/mL over a period of 24 h.     

Effect of permeation enhancers on transdermal delivery of fluoxetine: In vitro and in vivo evaluation

The aim of this study was to investigate the feasibility of transdermal fluoxetine (FX) delivery. The effects of chemical forms (base or salt) and permeation enhancers on in vitro skin permeation of FX were assessed using hairless mouse, rat and human cadaver skin. The optimized formulations from the in vitro studies were then evaluated in an in vivo pharmacokinetic study in rats. The in vitro skin permeation studies suggested that the FX base (FXB) and isopropyl myristate (IPM)–limonene mixture could be suitable for transdermal delivery of FX. The permeation parameters of FX through human cadaver skin were well correlated with that through hairless mouse and rat skin, suggesting that these animal models can be used for predicting the permeability of FX through human skin. After transdermal administration of FX with IPM or the IPM–limonene mixture to rats, the mean steady-state plasma concentration (C_ss) was 66.20 or 77.55 ng/mL, respectively, which was maintained over 36 h and had a good correlation with the predicted C_ss from the in vitro data. These in vitro and in vivo data demonstrated that permeation enhancers could be a potential strategy for transdermal delivery of FX.     

Influence of sonophoresis and chemical penetration enhancers on percutaneous transport of penbutolol sulfate

The effect of ultrasound and chemical penetration enhancers on transcutaneous flux of penbutolol sulfate across split-thickness porcine skin was investigated. Penbutolol sulfate is a potent, noncardioselective beta-blocker, which is used for the management of hypertension. The drug is one of the most lipid soluble of the β-adrenoceptor antagonists used clinically. It has an n-octanol/pH 7.4 buffer partition coefficient of 179 compared to a value of 22 for propranolol. The amount of penbutolol sulfate transported across the skin is low. In this project, we studied the effect of sonophoresis and chemical penetration enhancers on transdermal delivery of penbutolol sulfate. Low-frequency sonophoresis at a frequency of 20?kHz increased transcutaneous flux of penbutolol sulfate by 3.5-fold (27.37?±?μg?cm^?2?h^?1) compared to passive delivery (7.82?±?1.72?μg?cm^?2?h^?1). We also investigated the effect of 50% ethanol, 1% limonene and 2% isopropyl myristate (IPM) on transcutaneous permeation of penbutolol sulfate. IPM, ethanol and limonene at the concentration of 1%, 50% and 2%, respectively, increased the steady-state flux values of penbutolol sulfate 2.2- (17.07?±?3.24?μg?cm^?2?h^?1), 2.6?- (19.40?±?6.40?μg?cm^?2?h^?1) and 3.4-times (26.38?±?5.01?μg?cm^?2?h^?1) compared to passive delivery (7.76?±?2.9?μg?cm^?2?h^?1). The results demonstrate that although there were slight increases in flux values, ultrasound, ethanol, limonene and IPM did not significantly enhance the transdermal delivery of penbutolol sulfate. Future studies will examine ways of optimizing sonophoretic and chemical enhancer parameters to achieve flux enhancement.     

Effect of chemical enhancers on percutaneous absorption of daphnetin in isopropyl myristate vehicle across rat skin in vitro

The percutaneous absorption properties of daphnetin with chemical penetration enhancers were investigated to explore the feasibility of daphnetin as a candidate for transdermal delivery to treat arthritis. Permeation experiments were carried out in vitro using 2-chamber diffusion cells in isopropyl myristate (IPM) vehicle using rat abdominal skin as a barrier. Various enhancers were employed, including O-acylmenthol derivatives synthesized in the laboratory and many conventional enhancers. Among the O-acylmenthol derivatives, 2-isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) demonstrated a significant enhancing effect on daphnetin permeation. The highest degree of enhancement was obtained when NMP combined with Span 80 and the cumulative transport was 667.29 μg/cm² over 8 h. The solubility parameters, vehicle/stratum corneum partition, and diffusion coefficients were calculated to clarify the enhancing mechanism of classic enhancers on daphnetin. In conclusion, these findings allow a rational approach for designing an effective daphnetin transdermal delivery system.     

Terbutaline Transdermal Delivery: Preformulation Studies and Limitations of In-vitro Predictive Parameters

A transdermal dosage form of terbutaline may be useful to prevent nocturnal wheezing by providing prolonged duration of action. It will also improve patient compliance and bioavailability. Controlled input of the drug would be an additional advantage as this will reduce the intersubject variablity. Preformulation studies were conducted to determine the feasibility of a transdermal dosage form of terbutaline. The drug solubility in propylene glycol was 6.3 mg mL^?1. The apparent partition coefficient (n-octanol/deionized-water, pH 6.5) of terbutaline was 0.03. A pH-partition coefficient (octanol/buffer) profile indicated that the partition coefficient values were 0.02, 0.05 and 04 in buffers of pH 3, 7.4 and 9, respectively. The required drug flux through the human skin to attain therapeutic concentrations in the blood was calculated to be 3.3 μg cm^?2 h^?1 for a 10-cm² transdermal delivery system. Rabbit, guinea-pig and human skin was tested as the penetration barrier using modified Franz diffusion cells. Terbutaline flux values through the rabbit and guinea-pig skin were 8.3 and 7.7 μg cm^?2 h^?1, respectively. The flux through human full-thickness skin and human epidermis were 0.6 and 3.6 μg cm^?2 h^?1. Azone (3% w/v), a skin penetration enhancer, significantly increased the drug flux through all the membranes tested. Based on these studies, transdermal delivery of terbutaline appears to be promising.     

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.